The inner region of the mammalian adrenal gland is composed of sympathetic neurons that release the catecholamine hormones epinephrine and norepinephrine into the blood. During the fight-or-flight response, these hormones are released from the adrenal gland and prime the organism for the sudden demands that may be placed upon the circulatory, respiratory, musculoskeletal and metabolic control systems. Consistent with their wide-reaching actions, the inappropriate activity of the adrenal gland has been associated with a variety of diseases. These include hypertension (adrenal over-activity) and diabetes (adrenal under-responsiveness). The long-term objective of the proposed study is to determine the mechanisms that normally control the release of these adrenal hormones. One control pathway is believed to arise from the secretion of transmitters that are co-released with the catecholamines and that mediate a "short feedback loop" within the gland itself. The identity these co-transmitters and the condition(s) under which they released are not clear. However one strong candidate is neuropeptide Y, a polypeptide that is synthesized by chromaffin cells. Our hypothesis is that neuropeptide Y is an adrenal neurotransmitter whose release mediates a short feedback loop that regulates catecholamine secretion. To test this hypothesis we have 3 specific aims that we will address using murine sympathetic neurons (chromaffin cells) and adrenal slices. In the first set of experiments we will test the idea that the net effect of NPY is to increase the secretion of the catecholamines. Our second specific aim is to determine whether the release of NPY can regulate catecholamine release in an autocrine (cell-limited) manner. In the third set of experiments we will test the hypothesis that NPY can also regulate catecholamine secretion by altering the strength of the pre-synaptic input that normally limits catecholamine secretion. By using in vitro and in situ preparations and by employing electrophysiological and molecular techniques we will comprehensively test the hypothesis that a local feedback pathway controls catecholamine secretion. Although this work examines the regulation of the adrenal gland, similar mechanisms are likely to control the release of hormones from many different types of endocrine tissue. Project Narrative The inner region of the adrenal gland secretes hormones that regulate blood pressure and metabolism. Understanding how the release of these molecules is controlled is needed for the development of treatments that could correct their inappropriate or excessive release.